1. Field of the Invention
The present invention relates to a process for the preparation of compounds of the general formula I and their salts ##STR4##
wherein
R.sup.1 may represent H, (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.2 -C.sub.8)-alkoxyalkyl, (C.sub.1 -C.sub.8)-acyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, PA0 (C.sub.3 -C.sub.7)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -CB)-alkynyl, (C.sub.1 C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, or may contain hetero atoms such as N, O, P, S in the ring, PA0 aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, PA0 heteroaryl, such as furyl, pyrrolyl, pyridyl, PA0 heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, PA0 wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.1 -C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, PA0 N-bonded amino acid or peptide residue, PA0 R.sup.2 may represent H, (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.2 -C.sub.8)-alkoxyalkyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C.sub.3 -C.sub.7)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.1 -C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, PA0 aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, PA0 heteroaryl, such as furyl, pyrrolyl, pyridyl, PA0 heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, PA0 wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.1 -C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, PA0 R.sup.3 may represent H, ClCO, (C.sub.1 -C.sub.8)-acyl, which may optionally be linear or branched, PA0 a C-bonded amino acid or peptide residue or a conventional peptide-protecting group such as, for example, formyl, carbamoyl, benzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl. PA0 aryl, such as phenyl or naphthyl, PA0 aralkyl, such as benzyl or phenethyl, PA0 arylalkyloxy, such as benzyloxy, and R.sup.5 represents H, PA0 or R.sup.5 and R.sup.3 are bonded together via a C.dbd.O group to form a ring, wherein in formula V, when R.sup.2 is H, R.sup.3 may not be H, and to the uses of those intermediates. PA0 R.sup.1 may represent H, (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.2 -C.sub.8)-alkoxyalkyl, (C.sub.1 -C.sub.8)-acyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, PA0 (C.sub.3 -C.sub.7)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.1 -C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, PA0 aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, PA0 heteroaryl, such as furyl, pyrrolyl, pyridyl, PA0 heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, PA0 wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.1 -C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, PA0 N-bonded amino acid or peptide residue, PA0 R.sup.2 may represent H, (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.2 -C.sub.8)-alkoxyalkyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C.sub.3 -C.sub.7)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.1 -C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, PA0 heteroaryl, such as furyl, pyrrolyl, pyridyl, PA0 heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, PA0 wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkynyl, (C.sub.1 -C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, PA0 R.sup.3 may represent H, ClCO, (C.sub.1 -C.sub.8)-acyl, which may optionally be linear or branched, PA0 a C-bonded amino acid or peptide residue or a conventional peptide-protecting group such as, for example, formyl, carbamoyl, benzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl, PA0 by cyclising derivatives of the general formula II ##STR7## PA0 wherein R.sup.1, R.sup.2, R.sup.3 are as defined above and X represents an element from the group halogen, sulfonic acid ester, the desired compounds of the general formula I are obtained in good yields in a very simple and nevertheless advantageous manner, the process according to the invention being predestined for a large-scale industrial process owing to the fact that the starting materials necessary for the synthesis are relatively inexpensive, the reaction is simple to perform, the yields are good, and dangerous or foul-smelling reagents are not used. PA0 aryl, such as phenyl or naphthyl, PA0 aralkyl, such as benzyl or phenethyl, PA0 arylalkyloxy, such as benzyloxy.
The invention relates also to novel intermediates of the general formulae V, IV and II and their salts ##STR5##
wherein R.sup.1, R.sup.2, R.sup.3 are as defined above and R.sup.4 represents (C.sub.1 -C.sub.8)-alkyl, (C.sub.2 -C.sub.8)-alkenyl, (C.sub.2 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkenyloxy, which are optionally linear or branched and are optionally substituted by one or more halogen atoms,
2. Background Information
The compounds that can be prepared by the process according to the invention and the novel intermediates are valuable intermediates for the production of biologically active substances. For example, 3-amino-2-oxo-pyrrolidines are preferably used as a structural unit for peptide mimetics, which are used as pharmaceuticals. In WO 94/22820, 3-amino-1-phenyl-2-oxo-pyrrolidines substituted at the phenyl ring, for example, are described as intermediates for thrombocyte aggregation inhibitors. Other biologically active compounds containing those .gamma.-lactams have been studied by Kottirsch et al. (Bioorg. Med. Chem. Lett. 1993, 3, 1675). In other examples, they are used in highly potent neurokinin NK-2 receptor antagonists according to Deal et al. (J. Med. Chem. 1992, 35, 4195).
The majority of the processes used hitherto for the preparation of substituted 3-amino-2-oxo-pyrrolidines consist in first converting the corresponding open-chained methionine compounds into their sulfonium salts and cyclising the latter with strong bases in a suitable solvent. Friedinger et al. (J. Org. Chem. 1982, 47, 104-109) use for that purpose methyl iodide and sodium hydride, which is difficult to handle in a large-scale process. In U.S. Pat. No. 5,484,946, trimethylsulfonium or trimethylsulfoxonium salts are used for the alkylation instead of methyl iodide, which is readily volatile. The cyclisation is then carried out using potassium carbonate.
However, the main problem of those procedures, namely the unavoidable release from the methionine precursor of dimethyl sulfide, which is extremely strong-smelling, cannot be avoided in the process just mentioned either. Moreover, the necessary use of expensive aprotic polar solvents such as, for example, DMSO in the cyclisation with potassium carbonate appears to be a further disadvantage.
WO 94/22820 mentions a process in which racemic homoserine derivatives, which have been prepared starting from butyrolactone, are cyclised to pyrrolidones by means of triphenylphosphine and azodicarboxylic acid diesters. However, those reagents are not very suitable for use in an industrial process since they are relatively expensive. Moreover, the cyclisation in that variant yields a number of secondary products which are difficult and hence time-consuming and expensive to separate from the desired derivative (K. Nakajima et al. Peptide Chemistry 1983, 77-80).
Although L-homoserine is a naturally occurring amino acid, as yet there are known only a relatively small number of syntheses of homoserineamides, for example peptides, that start from homoserine. The reasons therefor are that homoserine and the corresponding N-acyl compounds very readily form the corresponding lactones under acid conditions (J. P. Greenstein, M. Winitz, "Chemistry of the Amino Acids", Wiley, New York 1961, Vol. 3, p. 2612). The same also occurs when the carboxy group is activated, as is necessary for the preparation of homoserineamides.
Although it is possible to react also N-acylhomoserinelactones with alkylamines and amino acid esters or amino acid salts to form the corresponding amides (Sheradsky et al., J. Org. Chem. 1961, 26, 2710), the reaction requires either very long reaction times or relatively high temperatures. For that reason, this method has not been used for the preparation of complex, optionally optically active compounds.
For the preparation of homoserineamides there are used homoserine derivatives in which the hydroxy function is protected by a suitable group. Hitherto, that was achieved either by a trityl group (Barlos et al., J. Chem. Soc., Chem. Commun. 1986, 1259), by mono- or di-methoxytrityl groups (Beltran et al., Lett. Pept. Sci. 1997, 4, 147), tert.-butyldimethylsilyl group (WO 97/46248) or benzyl groups (Cornille et al., J. Am. Chem. Soc. 1995, 117, 909). The disadvantage of those protecting groups is that they either require expensive chemicals or can be introduced only in a complicated manner.
O-Acyl compounds could be simple and inexpensive O-protecting groups. However, the problem with those compounds is that they very rapidly undergo an O-&gt;N-acyl shift under basic conditions, with formation of the corresponding N-acylhomoserines. Furthermore, for the preparation of O-acetylhomoserine there has hitherto been described only the reaction of homoserine with acyl anhydrides in perchloric acid which, on account of the explosive tendency of perchlorates, appears to be very disadvantageous and unsuitable for larger batches. The yields are only 51% at the most (Nagani et al., J. Biol. Chem. 1967, 242, 3884).